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Treatment of recurrent hepatitis C after liver transplantation: a pilot study of peginterferon alfa-2b and ribavirin combination
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Journal of Hepatology April 2004
See Editorial Below
Je´roˆme Dumortier1,*, Jean-Yves Scoazec2, Philippe Chevallier3, Olivier Boillot11Unite´ de transplantation he´patique—Fe´de´ration des Spe´cialite´s Digestives, Pavillon D, Hoˆpital Edouard Herriot, 69437 Lyon Cedex 03, France2Service d'anatomie pathologique, Hoˆpital Edouard Herriot, Lyon, France3Laboratoire d'Hygie`ne et d'Immunologie, Domaine Rockefeller, Lyon, France
Received 19 March 2003; received in revised form 4 December 2003;
accepted 17 December 2003
"..combination therapy was usually well tolerated... in order to improve the tolerance, we decided to progressively increase the doses of both pegylated interferon and ribavirin. PEG-IFN was given at 0.5 mg/kg/week weekly for 4 weeks, then at 1 mg/kg/week for the following months. Ribavirin was used at 400 mg daily for 4 weeks, then at 800 mg for the next 4 weeks and at 1000--1200 mg for the following months. With this strategy, only 4 patients (20%) withdraw combination therapy..."...precautions were taken to avoid rejections (see Author discussion below)... "Our strategy made it possible to perform combination therapy with optimal duration in 16/20... patients... This is likely to explain the good results we observed in terms of biochemical and virological responses... improvement in the histological lesions could be observed in all patients..."
EDITORIAL BY MANNS: "...In summary, the data presented by Dumortier et al. support current practice at many transplant centres worldwide. Combination therapy with pegylated interferon alpha and ribavirin appears to be safe, and a substantial rate of sustained virological response appears to be achievable. The first data using PEG-interferon/ribavirin combinationtherapy after liver transplantation are encouraging. However, many points remain currently unanswered and have to be addressed in further studies (see discussion at end of report)... Some of these questions are addressed by studies currently under way. We eagerly await the results of these ongoing studies..."
Introduction
Liver disease due to hepatitis C virus (HCV) is one of the main current indications for liver transplantation (LT). After LT for HCV-related cirrhosis, the recurrence of HCV infection is almost universal, and the risk of progression from chronic hepatitis to cirrhosis is accelerated: at 5 yearspost-OLT, more than 20% of patients have HCV-related severe graft damage.
Moreover, it has been suggested that HCV-related liver disease is more severe in the most recently transplanted patients. Donor age seems to be the major determinant of fibrosis progression rate. A pre-LT or early (preemptive) post-LT antiviral therapy is probably more effective than the treatment of a clinical hepatitis, but such treatment is usually not feasible.
In the aim to preserve liver graft viability, an early treatment of recurrent HCV hepatitis at the acute phase of the disease could be justified. In this indication, monotherapy with recombinant interferon-alfa (IFN) or ribavirin is known to be ineffective, but long-term combination therapy by IFNand ribavirin has been recently shown to give encouraging results.
Since it is now accepted that the standard therapy for hepatitis C is a combination therapy by ribavirin and pegylated alfa-interferon, especially in patients with HCV genotype 1 infection, it is important to evaluate the efficacy and tolerance of such a therapeutic regimen in transplanted patients with recurrent hepatitis C. We were therefore prompted to undertake a pilot study on tolerance and efficacy of a combination therapy with pegylated interferon alfa-2b (PEG-IFN) plus ribavirin in 20 patients with recurrent hepatitis C in the liver graft.
ABSTRACT
After liver transplantation (LT) for HCV-related cirrhosis, recurrence of HCV infection is universal and the risk of progression to cirrhosis is high. The modalities and efficacy of antiviral therapy in this indication are still controversial. We present here the results of a pilot study of a 12-month combination therapy by pegylated alfa2b-interferon (PEG-IFN) and ribavirin in 20 patients.
Twenty patients entered the study (13 male and 7 female, median age 53.8 years). In 80% of patients, HCV infection was of genotype 1. The delay between LT and antiviral therapy was 28 months.
The doses were progressively increased from 0.5 to 1 mg/kg/week for PEG-IFN and from 400 to 1000--1200 mg/d for ribavirin. Follow-up was basedon biochemical (ALT), virological (HCV-RNA) and histological (liver biopsy) examinations.
Four patients (20%) were withdrawn due to adverse effects. In 6 patients the dose of PEG-IFN had to be reduced to 0.5 mg/kg/week. A reduction in the dose of ribavirin in 13/16 cases was due to the onset of anemia.
Histological evidence of mild acute rejection increased the immunosuppressive regimen in 5/20 patients. At the end of the treatment, 75% of the patients had a biochemical response and 55% a virological response. SEE DETAILED ADDITIONAL RESULTS BELOW: 16 patients completed therapy and 11 had SVR.
The mean METAVIR score, according to activity and fibrosis, was A1.8 F2.2 before treatment and A0.3 F1.6 at the end of treatment.
In 9/20 patients, virological response persisted 6 months after the end of the treatment.
Our results suggest that combination therapy by PEG-IFN and ribavirin may be well tolerated and beneficial during recurrent hepatitis C in liver transplant recipients. They prompt the design of larger, prospective studies aiming to define the optimal duration of treatment and the need for maintenance therapy.
Patients and methods
From October 1990 to October 2001, LT was performed in 563 patientsin our institution; 97 had anti-HCV antibodies detected using a third generation radioimmunoblotting assay (RIBA). Sera were screened forHCV genotypes using Inno-lipa technique (Ingen). Follow-up wasconducted by using serum alanine aminotransferase (ALT) levels, serumHCV-RNA detection by polymerase chain reaction (PCR) for the 50 noncodingregion (Versant-HCV b-DNA 3.0-UI, Bayer Diagnostics, Puteaux,France), and liver biopsies (every 6 months when ALT levels were withinthe normal ranges, every 3 months when ALT levels were higher than theupper normal limit).
Indication for antiviral therapy was the evidence of histological featuresof ongoing HCV hepatitis on two consecutive liver biopsies; in all cases,histological lesions included portal and lobular inflammation, evidence ofboth piecemeal and intra-lobular hepatocellular necrosis, and presence ofportal and periportal fibrosis; necro-inflammatory lesions and fibrosis weregraded according to the METAVIR histological score; all treated patientshad a necro-inflammatory grade (A) >=2 and/or a fibrosis score (F) >=1.
During antiviral therapy, the immunosuppressive regimen was maintainedat usual levels. Since September 2000, a pilot study on the efficacy andtolerance of an antiviral therapy consisting in combined PEG-IFN andribavirin was started. Treatment with PEG-IFN and ribavirin (Schering-Plough) was initiated at low doses.
Ribavirin was used at 400 mg daily for 4 weeks, then at 800 mg for the next 4 weeks and at 1000--1200 mg for the following months; PEG-IFN was given at 0.5 mg/kg/week weekly for 4 weeks, then at 1 mg/kg/week for the following months. Doses were adjusted according to leukopenia, thrombocytopenia or anemia. Every month, hemoglobin, white cell count, platelets, prothombin time, blood urea nitrogen, serum creatinine, bilirubine and liver blood enzymes were performed. At 1, 3, 6, 12, and 18 months, HCV-RNA assay and liver biopsy were performed. The duration of combination therapy was 12 months, but could be modified according to tolerance. Informed consent was obtained from all patients.
The primary end point of the study was 6 months after having completed the treatment. The sustained virological response was defined by undetectable serum HCV-RNA.
Secondary end points included: the virological response at the end of treatment, serum ALT normalization (biochemical response) and improvement of liver histological lesions graded according to the METAVIR score (histological response). We examined the predictive value of the following parameters: age, sex, completion of treatment, PEG-IFN dosage, ribavirin dosage, initial serum ALT level, HCV genotype, initial HCV RNA levels, immunosuppressive regimen and initial liver damage. Variables were compared using the Fisher's exact test or the Mann--Whitney U test and considered assignificant if p <0.05.
Results
Characteristics of patients
The median age of the patients was 53.8 years. The median delay betweenLT and the beginning of the treatment was 28 months. The immunosuppressive regimen was maintained; a majority of patients (85%) received tacrolimus. Serum ALT was elevated in all but one patient. Eighty percent of the patients were infected with genotype 1. The liver biopsy disclosed moderate inflammatory activity and fibrosis according to theMETAVIR score (mean score A1.8 F2.2). None of the patients in the present study was treated previously with IFN or with IFN and ribavirin, after LT. Two patients have been treated with IFN and ribavirin before LT, both for less than six months because of side-effects, without virological response.
Effect of therapy on serum ALT and viral clearance
No patient died during the study period. Withdrawal of the treatment was observed in 4 patients (20%) because of thyroid disorder (n=1), depression (n=2), and severe asthenia (n=1), after, respectively, 1 (n=2), 2 (n=1)and 3 (n=1) months of treatment.
Among the 16 patients who completed the 12 month combination therapy, a reduction in the dosage of ribavirin was necessary because of anemia in 13, with a daily dosage of 200--400 mg in 7 and 600--800 mg in 6 patients. It was possible to achieve a daily dosage of 1000--1200 mg of ribavirin in only 3 patients. The dosage of PEG-IFN was 0.5 mg/kg/week in 6 and 1 mg/kg/week in 10 patients.
All patients presented a progressive reduction of serum ALT activity; 15 of the 20 patients (75%) had a biochemical response at the end of the treatment.
On an intention-to-treat basis, HCV-RNA was undetectable in the serum of 11/20 patients (55%) at the end of 12 months of treatment. All non-respondents to treatment were infected with genotype 1.
At the end of the 6 month follow-up period after the withdrawal of antiviral therapy, the virological response was maintained in 9 of the 11 respondent patients (82%).
Sustained virological response (SVR) was 9/20 (45%).
The 3-month viral load was predictive of SVR, since 10/11 patients with SVR had undetectable HCV-RNA in the serum versus 0/9 for the non-respondents.
From the different variables that were examined to determine whether they could predict virological response at the end of treatment, completion of the treatment and genotype 1 were significantly associated with viral clearance (p <0.05). The study was small but PEG- IFN (0.5 vs 1.0 ug/kg/wk & RBV dosing (<800mg/d vs >800 mg/day) did not appear to be significant predictors of response in this study, but perhaps in a larger study dosing would predict response.
SIDE EFFECTS DURING TREATMENT
Anemia 65%
Leukopenia 25%
Thrombocytopenia 20%
Weight loss
>10% of body wt 10%
Thyroid disorder 5%
Acute rejection 25%
Psych disorders 10%
Severe asthenia 5% (fatigue)
Histological data
All the patients of the study group underwent a liver biopsy at months 0, 1, 3, 6, 12 and 18. The biopsy at month 0 was compared, before beginning antiviral therapy, to the biopsies at month 12, at the end of PEG-IFN treatment, and at month 18, 6 months after withdrawal of treatment. Therewas no difference between METAVIR scores at months 12 and 18. The comparison of METAVIR score between M0 and M12 liver biopsy showed a significant improvement.
Before treatment, the mean METAVIR score, according to activity and fibrosis, was A1.8 F2.2. At the end of treatment, the METAVIR score had dramatically decreased: the mean score was A0.3 F1.6 (p <0.05) andimproved in all the patients. Liver biopsies during follow-up disclosed histological features of mild acute rejection in 5 patients; in all cases,rejection was treated by enhancement of the immunosuppressive regimen and resolutive.
Discussion by authors
The aim of this pilot study was to evaluate the efficacy and tolerance of combination therapy by pegylated alfa-2b interferon (PEG-IFN) and ribavirin for recurrent hepatitis C in transplanted patients.
The course of HCV infection after LT is now better understood. The reinfection of the graft is the rule. The risk of progression from chronic hepatitis to cirrhosis, leading to retransplantation or death, is increased as compared to non-transplanted patients. Moreover, the natural history ofthe disease is accelerated, likely as a result of the immunosuppressive treatment. In consequence, as recently confirmed by the data from the United Network for organ sharing, liver transplantation in HCV-positive recipients is associated with an increased rate of death and allograftfailure as compared to other indications. Such data justify an early and effective treatment of recurrent hepatitis C in order to preserve the viability of the liver graft.
The modalities of such a treatment remain controversial. Prophylaxis is the first option. In a recent study involving 21 patients receiving a prophylactic treatment by interferon and ribavirin, liver histology was normal in 81% of patients one year after LT, and virological clearance was observed in41% of the patients. However, these results have not been confirmed. Treatment of recurrent hepatitis C in the liver graft is a second option. Several strategies have been proposed. All published studies concur to show that the use of IFN monotherapy is unsuccessful to maintain sustainedbiochemical responses, which occurred in 23--28% of the patients. Leukopenia and thrombopenia were noted in all studies and resulted in dose reduction in some patients. Moreover, in the early report of Feray et al., chronic rejection may occur in patients under treatment (5/14), leading to retransplantation in some cases. Increasing the duration of treatment to 12 or 18 months, as observed in non-transplanted patients, may significantly increase the efficacy of the treatment.
Ribavirin monotherapy has also been proposed. In some studies, a biochemical response was obtained in 44--57% of the cases and may be associated with improvement of histological lesions; no rejection episodes were observed. Finally, combination IFN-ribavirin has been used in several studies. Encouraging results were reported in the initial study of Bizollon et al., with 100% of biochemical response and 48% of HCV clearance. However, most recent reports were less impressive, with a biochemical and virological response in 40--75% and 10--65% of the patients, respectively. A recent and comprehensive randomized study from Samuel et al. reported a sustained virologic response in 21% of transplant recipients with recurrent hepatitis C. This was probably related to a high rate (43%) of discontinued therapy due to adverse events (primarily ribavirin induced severe anemia). Moreover, in this study, there was no significant histological improvement.
It is now well accepted that the standard treatment of hepatitis C is the combination between pegylated interferon alfa-2a or alfa-2b and ribavirin. Few data are available about the tolerance and efficacy of this treatmentin transplanted patients with recurrent hepatitis C.
In our study, combination therapy was usually well tolerated. In view of previously reported results and in order to improve the tolerance, we decided to progressively increase the doses of both pegylated interferon and ribavirin. PEG-IFN was given at 0.5 mg/kg/week weekly for 4 weeks, then at 1 mg/kg/week for the following months. Ribavirin was used at 400 mg daily for 4 weeks, then at 800 mg for the next 4 weeks and at 1000--1200 mg for thefollowing months. With this strategy, only 4 patients (20%) withdraw combination therapy. This is better than previous data provided by studies using other treatments, which report 43% of treatment withdrawal. Among the remaining 16 patients, adverse side effects could be observed. The most frequent ones were anemia and leukopenia. In all cases, they were moderate and could be controlled by a reduction in the doses of either PEG-IFN orribavirin.
A major problem associated with IFN therapy in transplanted patients is the increased risk of cellular rejection, likely to be due to the immunomodulatory effects of the drug. This was one of the rationale for the progressive increase of IFN used in our study. Moreover, in our patients,after the initiation of combination therapy, the risk of acute rejection was carefully monitored by performing repeated liver biopsies, even in the absence of abnormalities of biological liver tests, and by measuring the serum levels of immunosuppressive drugs, which were maintained at thenormal upper limits. By using these precautions, in our study, 5 patients had evidence of acute rejection. In all cases, rejection was mild and could be treated only by increasing the immunosuppressive regimen. There is noevidence of chronic rejection in any of our treated patients.
Our strategy made it possible to perform combination therapy with optimal duration in 16/20 patients. In a majority of patients, reduction of doses of either IFN (6 cases) or ribavirin (13 cases) was necessary but a12-month duration of treatment could nevertheless be achieved. This is likely to explain the good results we observed in terms of biochemical and virological responses.
Indeed, 75% of patients had a biochemical response at the end of the treatment, 55% had a virological response, which was sustained in 82%. These results have to be compared with our previous results with standard IFN and ribavirin; we reported from 24 patients, a virological response at theend of treatment in 50% of the patients. The virological response at the end of therapy in the present study (55%) was not that different from that obtained with standard IFN-ribavirin and this could be due to a majority ofgenotype 1 infection (95.8%) in the present study group. In the present study, virological response was associated with completion of the 12-month treatment, and to HCV genotype.
Moreover, improvement in the histological lesions could be observed in all patients; this was confirmed by the significant decrease in the mean METAVIR score observed at the end of the treatment. This is encouragingwhen compared to the recently reported studies using standard IFN and ribavirin combination, which reported not more than 20% of virological response and no histological response.
In conclusion, the results of this pilot study strongly suggest that a combination therapy by PEG-IFN and ribavirin may be well tolerated and beneficial during recurrent hepatitis C in recipients with liver transplant.They prompt the design of larger, prospective studies aiming to define the optimal duration of treatment and the need for maintenance therapy.
Editorial
Changing faces—natural course and treatment of hepatitis C after liver transplantation
J. Bahr, Michael P. Manns*
Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Carl-Neuberg-Strasse 1, 30623 Hannover, Germany
Orthotopic liver transplantation (OLT) is an efficient treatment for patients with end-stage liver disease currently reaching 5-year survival rates of more than 70%. However, the improved control of many of the short-term problems after OLT shifted the focus of interest to the long-term complications. Chronic hepatitis C represents the most abundant single diagnosis in patientsundergoing OLT. Therefore, recurrence of hepatitis C after OLT has been and is a major issue in transplantation medicine. In this issue of the Journal Dumortier and co-workers present their experience using combination therapy with pegylated interferon alpha and ribavirin, thus opening a new round in the fight against recurrent hepatitis C after OLT.
In the immunocompetent host, chronic hepatitis C is a slowly advancing disease taking decades to progress to liver cirrhosis. After OLT, recurrence of the virus is nearly universal and viral load is considerably higher than prior to transplantation. The impact of recurrent hepatitis C on the prognosis of patients after OLT has been a point of intensive discussion for many years. Early reports found that a small proportion of patients (approx. 5%) suffer from a rapidly progressing cholestatic hepatitis similar to fibrosingcholestatic hepatitis (FCH) which had been detected in immunosuppressed patients with hepatitis B. However, the remaining patients appeared to have a favourable prognosis and progression to cirrhosis was rarely detected. It was the landmark work of Berenguer and co-workers, who recently demonstrated that the rate of fibrosis progression might have increased depending on the date of OLT. Their results suggested that posttransplanthepatitis C has changed from a snail to a cheetah with respect to the speed of disease progression.
In other words, the median time interval between OLT and detection of livercirrhosis shortened from more than 10 years in patients transplanted in the late 1980s to around 3 years in patients transplanted in the late 1990s. Meanwhile, these results have been confirmed by other centres. Once cirrhosis is established, signs of decompensation develop quickly.
Additionally, recent data suggest an impaired survival of patients with hepatitis C after OLT which is not caused by recurrence of hepatocellular carcinoma. Various explanations have been suggested for these findingsincluding changes in the selection of patients and in postoperative care. However, the most important factor appears to be the recent acceptance of elderly donors since there is a strong correlation between donor age and the course of recurrent hepatitis C after OLT.
The lack of an efficient strategy to prevent reinfection of the graftand the increasingly aggressive course of hepatitis C after OLT indicate the need for an effective antiviral therapy. Several approaches have been proposed to prevent the progression of posttransplant hepatitis C to liver cirrhosis.
It was attempted to reduce viral load or eliminate HCV in patients on the waiting list for OLT using either standard interferon alpha monotherapy or standard interferon alpha/ribavirin combination therapy. In treated patients, a virological response can be expected in up to one third of the patients, and 20% remain free of virus after OLT. However, many patients do not meet inclusion criteria, and serious adverse events occur frequently, mostlydue to low platelet counts.
Treatment may be initiated in the first weeks after liver transplantation prior to the onset of biochemical or histological signs of recurrent hepatitis (preemptive/prophylactic therapy). Although effective in some patients and apparently not associated with a grossly increased rate of acute rejections, data supporting this approach are scarce. Pegylated interferons have not been used, and preemptive therapy was not directly compared todelayed treatment. Additionally, the tolerability of the treatment is limited in the early posttransplantation period. Therefore, most transplantation centres currently follow protocols that initiate treatment once signs or symptoms of recurrent hepatitis C develop.
Standard interferon alpha treatment of recurrent hepatitis C after OLT was evaluated at many centers. The study groups were mostly small and uncontrolled. However, the overall picture is unequivocally unfavourable forstandard interferon monotherapy, because viral clearance is rarely achieved. Initially, concern was raised as to the immunological safety of interferon use after OLT. Although induction of rejection was reported, careful histologicalevaluation prior to interferon therapy appears to keep the risk low, and severe rejection episodes are a rare event.
Monotherapy using ribavirin was similarly ineffective as interferon with regard to viral clearance rates. Treatment results improved when combination therapy with standard interferon alpha and ribavirin was introduced. Seven papers with study groups of more than 25 patients have been published. Intent-to-treat analysis showed average sustained virological responserates of around 20%. The main obstacle in achieving better results is formed by the frequent occurrence of untoward effects requiring dose reduction or even cessation of combination therapy. The most common side effects were either anaemia or leukopenia, which opened the discussionwhether growth factors like erythropoetin or GSF should be used.
Many centres currently use pegylated interferon either as monotherapy or combined with ribavirin in patients with recurrent hepatitis C. However, published data on this treatment are scarce. Apart from preliminary data presented at meetings no regular papers are currently available. Now,Dumortier et al. present the Lyon data on combined treatment with pegylated interferon alpha 2b and ribavirin. Of 20 patients treated, nine (45%) experienced a sustained virological response. These effects were mirroredby histological improvements.
The main predictors of success were the viral genotype and the completion of the treatment course. This underlines the need for adherence ofthe patients to the treatment. However, the study was uncontrolled and the number of patients treated is limited.
Side effects requiring dose reductions occurred in the majority of patients. Two other points regarding safety and tolerability of the treatment should be mentioned. Firstly, the protocol used an increasing dosing scheme for both ribavirin and interferon to reduce early side effects. This contrasts to the current discussion on an intensified induction phase to increase response rates. However, all but one responders showed viral clearance after 3 months of treatment. The second point is the high number of liverbiopsies performed (six per patient). Acute rejection episodes were found in 20% of the patients but did not require cessation of the treatment. These data are reassuring with regard to the immunological safety of pegylated interferon in patients after liver transplantation.
In summary, the data presented by Dumortier et al. support currentpractice at many transplant centres worldwide. Combination therapy with pegylated interferon alpha and ribavirin appears to be safe, and a substantial rate of sustained virological response appears to be achievable.
The first data using PEG-interferon/ribavirin combinationtherapy after liver transplantation are encouraging.
However, many points remain currently unanswered and have to be addressed in further studies. The results need confirmation in a controlled study including a sufficient number of patients. An increasing number of patients has received antiviral therapy prior to and after OLT. Are theredifferences between non-responders and naı¨ve patients? The optimal timing of therapy remains unclear. Should we favour preemptive therapy and how long do we need to treat? As dose reductions are required in many patients, the role of additional therapies like erythropoetin and other growth factors needs to be clarified. Even though combination therapy may not achieve sustained virological responses in the majority of the patients it needs to beevaluated whether fibrosis progression may be slowed down by continuing interferon treatment. Some of these questions are addressed by studies currently under way. We eagerly await the results of these ongoing studies.
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